Pancreatic cancer is the fourth leading cause of cancer death in the United States. The incidence and mortality rates are nearly equivalent due to the paucity of effective treatment options and, accordingly, new therapies are desperately needed.(1, 2) Numerous studies have demonstrated the key role that Ras signaling plays in pancreatic cancer cell growth and development, with >90% of pancreatic adenocarcinoma manifesting activating Ras mutations. (3) Ras activation has multiple effects, predominantly through three major pathways, the MAPK, AKT, and RAL pathways. (4) Our group and others have shown that RAL signaling is an important pro-survival signaling pathway in pancreatic cancer and that CDK5 is another activator of RAL signaling.(3, 5, 6) We detail a clinical trial tha aims to disrupt the Ras signaling system by using concurrent inhibition of two of the three key downstream pathways of Ras. We propose a Phase I study of the combination of MK2206, an Akt inhibitor, and dinaciclib, a potent multi-CDK inhibitor, in advanced pancreatic cancer with an added expansion cohort to assess for preliminary efficacy and translational endpoints. The first cohort of this study will be to determine the maximum tolerated dose (MTD) and the safety and toxicity profiles for this combination in pancreatic cancer. An expansion cohort at that MTD will subsequently be enrolled to assess the preliminary efficacy of this combination as well as multiple correlative endpoints. Patients in the expansion cohort will be randomized to receive single agent therapy for one week, followed by combination treatment from that point onwards with serial blood sampling and tumor biopsies pre- and post-treatment. This strategy allows for pharmacokinetic and pharmacodynamic analyses prior to treatment, after initiation of single agent, and after addition of the second agent. Pharmacodynamic endpoints will focus on AKT and RAL pathway effectors and endpoints as both proof-of-target and potential use as predictors of therapeutic benefit for future studies of this regimen. This is a novel approach to target pancreas cancer by inhibiting two key downstream pathways of Ras based on strong preclinical data. Our goal is to increase the survival of patients with pancreatic cancer by providing a new treatment option for this lethal disease.